The collective term “cancer” covers numerous different malignant diseases, which are characterized by the fact that the cells grow in an uncontrolled way, cell differentiation is absent, adjacent tissues are invaded, and metastases are formed. Almost every tissue can be the starting point of such a malignant disease.
Despite continuous progress, the current standard cancer treatments with antineoplastic active ingredients involve considerable detriments and risks for the patients. Owing to their unspecific antiproliferative effect and high dosage, these antineoplastic agents damage not only tumor cells but also rapidly growing healthy cells, such as for example mucous membranes, cells in the hemopoietic system (the bone marrow), and hair follicles. Treatment with antineoplastic agents is therefore generally associated with strong side effects, which detracts from the general well-being of the patients (acute side effects), cause irreversible damage to healthy tissue, and increase the risk of secondary tumors. Furthermore, tumors can build up resistance to active ingredients, which reduces the activity when a patient is treated with multiple dosages.
To obtain greater activities and reduce the development of resistance, a number of active ingredients are often combined and used for treatment at the same time (polychemotherapy). Despite this strategy, the problems described above have not been satisfactorily solved yet. It is therefore urgently required from the economic and medicinal viewpoint to find new and damage-free treatments for the fight against cancer.
A possible basis for the treatment of such malignant diseases is the reduction of the glutamine concentration in the bloodstream. Glutamine is the most common amino acid in the bloodstream and plays a decisive role as a source of nitrogen and energy, as well as a basic component of many synthetic processes in the cells. Owing to their vigorous growth, tumor cells are particularly dependent on glutamine in the bloodstream for use as a substrate in the biosynthesis of nucleotides and proteins, for energy generation, and for the production of metabolic intermediates in key positions of their metabolic pathways.
Numerous attempts were made in the 1980s to base cancer therapy on glutamine-cleaving enzymes or reactive glutamine analogs that deprive the tumor of its necessary glutamine. Roberts et al. showed that pseudomonas 7A glutaminase-asparaginase possesses an antineoplastic activity against numerous leukemic disorders in rodents, as well as against ascites tumors and certain solid tumors (DE 41 40 003 A1 and WO 94/13817 A1). In addition, it was found in animal experiments on athymic mice that the combination of glutamine analogs (e.g. 6-diazo-5-oxo-L-norleucine or DON) with glutaminase inhibits colon, breast and lung cancer in humans [W. McGregor and J. Roberts, Proc. Anal. Assoc. Cancer Res., 30 (1989), p. 578]. It was also shown that treatment with glutaminase delayed the development of resistance to methotrexate [J. Roberts, F. A. Schmid and H. J. Rosenfeld, Cancer Treat. Rep., 63 (1979), pp. 1045-1054].
However, the initially promising animal experiments did not lead to marketable medicaments, since therapeutical approaches using glutaminase or glutamine analogs (e.g. DON, acivicin) had to be discontinued initially, owing to severe toxic side effects (M. A. Medina: “Glutamine and Cancer”, The Journal of Nutrition, vol. 131, No. 9, (2001), pp. 2539s-2542s). Despite the ideal concept of a glutamine depletion therapy, it has not been possible so far to achieve acceptance of a treatment based on proteins with a glutaminase activity.
However, since cancer still cannot be treated satisfactorily, it is of great medical and economic importance to find a way of using the promising concept of glutamine depletion therapy in future.